Tridimensional infiltration of DNA viruses into the host genome shows preferential contact with active chromatin

Pierrick Moreau,Shogofa Mortaza,Axel Cournac,Marc Lavigne,Romain Koszul,Martial Marbouty,Christine Neuveut,Stefano Cairo,Agnes Thierry,Gianna Aurora Palumbo

doi:10.1038/s41467-018-06739-4

Abstract

Whether non-integrated viral DNAs distribute randomly or target specific positions within the higher-order architecture of mammalian genomes remains largely unknown. Here we use Hi-C and viral DNA capture (CHi-C) in primary human hepatocytes infected by either hepatitis B virus (HBV) or adenovirus type 5 (Ad5) virus to show that they adopt different strategies in their respective positioning at active chromatin. HBV contacts preferentially CpG islands (CGIs) enriched in Cfp1 a factor required for its transcription. These CGIs are often associated with highly expressed genes (HEG) and genes deregulated during infection. Ad5 DNA interacts preferentially with transcription start sites (TSSs) and enhancers of HEG, as well as genes upregulated during infection. These results show that DNA viruses use different strategies to infiltrate genomic 3D networks and target specific regions. This targeting may facilitate the recruitment of transcription factors necessary for their own replication and contribute to the deregulation of cellular gene expression.

Highlights

Whether non-integrated viral DNAs distribute randomly or target specific positions within the higher-order architecture of mammalian genomes remains largely unknown
Upon internalization and transfer to the nucleus, the relaxed circular partially double-stranded DNA (RC-DNA) is converted into covalently closed circular DNA5. cccDNA is a template for all hepatitis B virus (HBV) transcripts including pre-genomic RNA (pgRNA) and is organized into a chromatin-like structure associated with histone and non-histone proteins[6]
primary human hepatocytes (PHH) contact maps generated using independent donors show that A and B compartments remain unchanged during infection (Fig. 2a), which does not induce large-scale reorganization of hepatocyte genomes

Summary

Introduction

Whether non-integrated viral DNAs distribute randomly or target specific positions within the higher-order architecture of mammalian genomes remains largely unknown. HBV contacts preferentially CpG islands (CGIs) enriched in Cfp[1] a factor required for its transcription These CGIs are often associated with highly expressed genes (HEG) and genes deregulated during infection. Ad5 DNA interacts preferentially with transcription start sites (TSSs) and enhancers of HEG, as well as genes upregulated during infection These results show that DNA viruses use different strategies to infiltrate genomic 3D networks and target specific regions. We applied Hi-C9 and viral DNA capture (CHi-C) on primary human hepatocytes (PHH) infected by HBV or Hi-C on PHH infected by adenovirus type 5 (Ad5) to investigate the spatial nuclear organization of the viral DNAs. We showed that while both viral DNAs contact preferentially active chromatin, they adopt different strategies. We demonstrated that Ad5 interacts preferentially with transcription start sites (TSSs) and enhancers of highly expressed genes and genes upregulated during infection

Methods

Results

Conclusion